Epidermolysis bullosa is a group of inherited mechanobullous disorders characterized by fragility of the skin within the cutaneous basement membrane zone, with considerable clinical and genetic heterogeneity, inherited either in an autosomal dominant or autosomal recessive fashion. Traditionally, EB has been divided into three broad categories based on the level of tissue separation, determined by diagnostic electron microscopy and/or immunoepitope mapping (Fine et al., 2000): the simplex forms of EB (EBS) demonstrate tissue separation within the basal keratinocytes at the bottom layer of epidermis; the junctional forms of EB (JEB) display cleavage within the lamina lucida in the dermoepidermal basement membrane; and in the dystrophic forms (DEB), tissue separation occurs below the lamina densa within the upper papillary dermis (Varki et al., 2007).
DEB is caused by mutations in COL7A1 (OMIM *120120), on chromosomal region 3p21, encoding type VII collagen. It is either dominantly or recessively inherited. The recessive form, RDEB (OMIM #226600) is one of the most severe genodermatoses in children and young adults. The dominant form, DDEB (OMIM #131750) is usually less severe. DEB patients suffer since birth from loss of adhesion between the epidermis and the dermis resulting in severe blistering of the skin and mucosae after mild trauma. The disease leads to severe local and systemic complications, and the prognosis is poor because of the increased risk of aggressive skin cancer. Indeed, over 50% of affected individuals will die before the age of 40-years directly due to metastatic squamous cell carcinoma (Fine et al., 2000). There are 4 subtypes of RDEB: the severe generalized type (Hallopeau-Siemens) which is the most severe, the generalised non-severe (mitis) form, the inversa form (which involves mainly the flexures), and the centripetalis (localised) form. All these clinical variants are caused by loss of function mutations in COL7A1, which result in structural defects in anchoring fibrils (Hilal et al., 1993; Hovnanian et al., 1992). Type VII collagen is the major component of anchoring fibrils which are key attachment structures for dermo-epidermal adhesion.
Type VII collagen is synthesized as a 290-kDa protein precursor. The protein has a homotrimeric quaternary structure, and each of the three identical αl-chains consists of three major domains: the 130-kDa globular, non collagenous domain 1 (NC1) at the amino terminus, the helical, collagenous domain of 140 kDa, and the small non collagenous domain 2 (NC2) at the carboxy terminus. In the extracellular matrix, type VII collagen further assembles into antiparallel dimers, with the helical portions disulfide-bonded at a short carboxy terminal overlap that places the amino terminal globular domains at opposite ends. The NC1 globular domain is encoded by exons 2 to 27. The central collagenous domain is encoded by exons 28 to 112 and folds into an interrupted collagen triple helix. The larger interruption in the periodic Gly-X-X collagenous sequence is the so-called hinge segment, encoded by exons 71 and 72. With a predicted α-helical structure, it is thought to confer flexibility to the molecule. The NC2 domain is encoded by exons 113 to 118. The NC2 domain is required for the trimerisation of the al chains and for the antiparallel dimerisation of the homotrimers.
The gene encoding type VII collagen, COL7A1, is segmented into 118 exons and spreads over 32 kb on human chromosome 3p21. The shortest exons are 27-nucleotides long while the longest attains a length of 201 nucleotides. Computational analysis of the genomic sequence revealed that COL7A1 is particularly suited for exon skipping strategy. Among the 118 exons, exons 28 to 112 are in frame, which means that skipping of any of these exons while preserving the reading frame of the mRNA is theoretically feasible.
No specific treatment is available for Dystrophic Epidermolysis Bullosa but the targeted removal of exons carrying recurrent mutations shows therapeutic potential.